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Deciphering the Pathogenesis of Acute Myeloid Leukemia

Reckzeh, Kristian LU (2012) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2012:37.
Abstract (Swedish)
Popular Abstract in Swedish

Leukemi är en cancersjukdom i blod och benmärg som karakteriseras av en störd blodbildning. Vid normal blodbildning delar sig ett begränsat antal omogna blodceller så kallade blod stamceller (eller hematopoietiska stamceller) och mognar till funktionella blodceller. Genom att dela sig utan att mogna har stamcellerna även potential till at förnya sig själva. När nya stamceller och mogna celler samtidigt bildas kan en kontinuerlig blodproduktion upprätthållas genom livstiden. Då leukemi uppstår mognar blodcellerna inte fullt ut, vilket leder till en anhopning av omogna celler med brist av funktionella blodceller som följd. Ett fåtal leukemiska stamceller tros ligga bakom den maligna expansionen.... (More)
Popular Abstract in Swedish

Leukemi är en cancersjukdom i blod och benmärg som karakteriseras av en störd blodbildning. Vid normal blodbildning delar sig ett begränsat antal omogna blodceller så kallade blod stamceller (eller hematopoietiska stamceller) och mognar till funktionella blodceller. Genom att dela sig utan att mogna har stamcellerna även potential till at förnya sig själva. När nya stamceller och mogna celler samtidigt bildas kan en kontinuerlig blodproduktion upprätthållas genom livstiden. Då leukemi uppstår mognar blodcellerna inte fullt ut, vilket leder till en anhopning av omogna celler med brist av funktionella blodceller som följd. Ett fåtal leukemiska stamceller tros ligga bakom den maligna expansionen. Konventionell leukemibehandling minskar mängden omogna celler men förefaller inte vara verksam på de leukemiska stamcellerna. De leukemiska stamceller som blir kvar efter behandling förmodas vara den bakomliggande orsaken till återfall. Akut myeloisk leukemi (AML) är en typ av leukemi där man känner till flera genetiska förandringar (mutationer) som förekommer i de maligna blodcellerna. För att bättre kunna forstå uppkomst av AML har vi upprättat en musmodell för human AML genom att föra in tre vanligt förekommande mutationer i det genetiska materialet hos musens blodceller. Vår modell tillåter molekylära och cellulära studier både före och under manifestationen av sjukdomen. Jämfört med tidigare modeller representerar vår modell orsaken till leukemien på ett bättre sätt.

Våra resultat och de framtida studier de kommer att leda till kan bidra till nya framtida terapier i kampen mot AML. Dessutom kan musmodellen användas för att studera innovativa och oprövade läkemedel. (Less)
Abstract
Acute myeloid leukemia (AML) is a malignant disorder of the blood system. Hematopoietic stem cells (HSCs) supply and maintain this system by differentiating via intermediates into lineage-restricted progenitors that strongly proliferate to keep up with the high turn-over of mature blood cells. In AML, the mechanisms controlling differentiation and proliferation of myeloid cells are disturbed leading to the accumulation of undifferentiated cells that interfere with the production of normal blood cells.

Mutations of the transcription factor C/EBPα have been observed in 10 percent in AML with normal cytogenetics. In addition, internal tandem duplications (ITD) of FLT3 are frequently observed alterations in AML and coincide with... (More)
Acute myeloid leukemia (AML) is a malignant disorder of the blood system. Hematopoietic stem cells (HSCs) supply and maintain this system by differentiating via intermediates into lineage-restricted progenitors that strongly proliferate to keep up with the high turn-over of mature blood cells. In AML, the mechanisms controlling differentiation and proliferation of myeloid cells are disturbed leading to the accumulation of undifferentiated cells that interfere with the production of normal blood cells.

Mutations of the transcription factor C/EBPα have been observed in 10 percent in AML with normal cytogenetics. In addition, internal tandem duplications (ITD) of FLT3 are frequently observed alterations in AML and coincide with mutations of C/EBPα.

The effects of FLT3-ITD cooperation with C/EBPα mutations in AML are not fully understood. To address this, knockin mouse strains harboring different Cebpa mutations and Flt3-ITD were used to generate an AML mouse model. This model demonstrated a block at the transition from pGMP to GMP due to disrupted C/EBPα function. The cooperative effect of FLT3-ITD is composed of enhancing the generation of leukemia-initiating GMPs and activation of STAT5 targets. In in vitro studies it was demonstrated that FLT3-ITD reduces the cytokine-requirements for cell growth and that leukemic cells harboring FLT3-ITD are more sensitive to inhibition of the FLT3 pathway in vitro. To address the impact of FLT3-ITD gene dosage and loss of Flt3 wild type allele in vivo the Flt3-ITD knockin mouse was crossed to the Flt3 receptor knockout mouse. These studies demonstrated that the myeloproliferative phenotype was FLT3-ITD dosage-dependent and independent of FL. In summary, the data presented provide deeper insights into oncogene cooperation and FLT3-ITD dosage in AML. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Porse, Bo, Finsen Laboratory, University of Copenhagen
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Hematopoiesis, Hematopoietic Stem Cell, AML, FLT3, C/EBPalpha
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2012:37
pages
100 pages
publisher
Division of Molecular Medicine and Gene Therapy, Dept of Laboratory Medicine
defense location
Belfragesalen, D15, BMC.
defense date
2012-05-03 10:00
ISSN
1652-8220
ISBN
978-91-86871-99-4
language
English
LU publication?
yes
id
33d32ebd-082c-424e-8725-19e3f0c6a4b7 (old id 2438633)
date added to LUP
2012-04-18 07:48:35
date last changed
2016-09-19 08:44:45
@phdthesis{33d32ebd-082c-424e-8725-19e3f0c6a4b7,
  abstract     = {Acute myeloid leukemia (AML) is a malignant disorder of the blood system. Hematopoietic stem cells (HSCs) supply and maintain this system by differentiating via intermediates into lineage-restricted progenitors that strongly proliferate to keep up with the high turn-over of mature blood cells. In AML, the mechanisms controlling differentiation and proliferation of myeloid cells are disturbed leading to the accumulation of undifferentiated cells that interfere with the production of normal blood cells.	<br/><br>
Mutations of the transcription factor C/EBPα have been observed in 10 percent in AML with normal cytogenetics. In addition, internal tandem duplications (ITD) of FLT3 are frequently observed alterations in AML and coincide with mutations of C/EBPα.	<br/><br>
The effects of FLT3-ITD cooperation with C/EBPα mutations in AML are not fully understood. To address this, knockin mouse strains harboring different Cebpa mutations and Flt3-ITD were used to generate an AML mouse model. This model demonstrated a block at the transition from pGMP to GMP due to disrupted C/EBPα function. The cooperative effect of FLT3-ITD is composed of enhancing the generation of leukemia-initiating GMPs and activation of STAT5 targets. In in vitro studies it was demonstrated that FLT3-ITD reduces the cytokine-requirements for cell growth and that leukemic cells harboring FLT3-ITD are more sensitive to inhibition of the FLT3 pathway in vitro. To address the impact of FLT3-ITD gene dosage and loss of Flt3 wild type allele in vivo the Flt3-ITD knockin mouse was crossed to the Flt3 receptor knockout mouse. These studies demonstrated that the myeloproliferative phenotype was FLT3-ITD dosage-dependent and independent of FL. In summary, the data presented provide deeper insights into oncogene cooperation and FLT3-ITD dosage in AML.},
  author       = {Reckzeh, Kristian},
  isbn         = {978-91-86871-99-4},
  issn         = {1652-8220},
  keyword      = {Hematopoiesis,Hematopoietic Stem Cell,AML,FLT3,C/EBPalpha},
  language     = {eng},
  pages        = {100},
  publisher    = {Division of Molecular Medicine and Gene Therapy, Dept of Laboratory Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Deciphering the Pathogenesis of Acute Myeloid Leukemia},
  volume       = {2012:37},
  year         = {2012},
}